Project Summary Mitochondrial function declines with age and is exacerbated in disease states such as Parkinson's. One potential cause of the mitochondrial decline is the propagation of deleterious mitochondrial genomes (mtDNAs) throughout an organism's lifetime as has been observed in individual muscle cells or dopaminergic neurons. mtDNAs only encode respiratory chain and ATP synthase components and thus lesions result in oxidative phosphorylation (OxPhos) deficiency. Because mtDNAs exist at 100s-1000s of copies per cell, a lesion in a single genome is well tolerated. However, if the deleterious genome accumulates to greater than ~60%, pathology related to OxPhos dysfunction ensues including cell degeneration and death. It is currently unclear how deleterious mtDNAs are maintained, how they are propagated and ultimately why they are toxic. One mechanism by which cells respond to OxPhos deficiency is by activating the mitochondrial unfolded protein response (UPRmt), which initiates a mitochondrial repair and recovery program. We have found that UPRmt activation provides protection against OxPhos deficiencies caused by nuclear mutations in OxPhos genes or against bacterial derived toxins (P. aeruginosa produces cyanide for example). Our surprising preliminary data indicate that the UPRmt is required to maintain and propagate deleterious mtDNAs in a C. elegans model of heteroplasmy. Therefore, we hypothesize that deleterious mtDNAs are selfish, or parasitic, and take advantage of an endogenous stress response program in place to repair and respond to mitochondrial dysfunction. Here, we plan to examine the consequences of UPRmt activation and deleterious mtDNA propagation as a contributor to age-associated mitochondrial dysfunction.